Psoriasis
Inflammatory skin conditions include psoriasis, keloid (hypertrophic scar), atopic dermatitis, lichen simplex chronicus, prurigo nodularis, Reiter syndrome, pityriasis rubra pilaris, pityriasis rosea, stasis dermatitis, rosacea, acne, lichen planus, scleroderma, seborrheic dermatitis, granuloma annulare, rheumatoid arthritis, dermatomyositis, alopecia areata, lichen planopilaris, vitiligo, and discoid lupus erythematosis. Psoriasis is a common skin condition with a prevalence of 1–2% in the general population. The disease is of undetermined etiology and affects patients of all ages with no gender preference. The most common presentation is plaque psoriasis, which is characterized by well-demarcated, erythematous plaques with scale on the extensor surfaces of the extremities, especially the elbows and knees, and the scalp. The plaques are highly vascularized and frequently bleed with mechanical removal of the scale (Auspitz sign). Histologically, the plaques have a characteristic epidermal hyperplasia with rete ridges hyper-extending in a regular fashion into the dermis and the intervening epidermis. The abnormal hyperplasia of the epidermis results in the characteristic scale due to incomplete terminal differentiation of keratinocytes. Neutrophils may also be typically found within the scale layers and may occasionally contribute to a pustular presentation. A lymphocyte predominant inflammatory infiltrate is present which is usually limited to the superficial plexus of blood vessels in the skin. (Dosik J, Shupack J Current Dermatologic Diagnosis and Treatment, edited by I M Reedberg and M R Sanchez. Philadelphia: Current Medicine Inc. 2001. pp.178–179).
Subcategories of psoriasis include pustular psoriasis, inverse psoriasis, guttate psoriasis, nail psoriasis, psoriatic arthritis, and exfoliative erythrodermic (Von Zumbusch) psoriasis. Pustular psoriasis is characterized by neutrophil predominance, pustule formation and sometimes systemic symptoms. Inverse psoriasis presents in intertriginous areas. Guttate psoriasis characteristics include a widespread presentation on the body, truncal lesions, small teardrop lesions, and eruptive lesions. Psoriatic arthritis is usually an asymmetric oligoarthritis. Exfoliative, or Von Zumbusch, psoriasis is a life threatening form. (see Dosik et al. supra).
The existing treatments for psoriasis are targeted at the major histopathologic components of the disease. Broad immunosuppression or T-lymphocyte specific immunosuppression is achieved by treatment with UVB, cyclosporine, methotrexate, topical steroids, and other immunosuppressive modalities. Keratinocyte terminal differentiation is targeted by calcipotriene and salicyclic acid. Retinoids target both immunosuppression and keratinocyte terminal differentiation. A drawback to many of the agents currently employed to treat psoriasis is that they must be administered by injection or in the hospital. Orally administered treatments have a better rate of patient compliance and are therefore preferable as compared to treatments that are administered via the intravenous route.
Oral treatments for inflammatory skin conditions are also preferable to topical treatments. Topical treatments are often ineffective because of washing or rubbing away from the affected area. Patients are inconvenienced by staining of clothes and furniture by topical treatments, and by the need to cover the affected area with occlusive or bulky dressings. Oral treatments have a better rate of patient compliance than topical treatments because they are more convenient. Orally administered treatments provide more reliable drug delivery because the problem of washing or rubbing away of topical treatments is avoided.
Poor efficacy and high recurrence rates are also common problems of existing treatments for psoriasis. Few treatments are rapid acting or cause the disease to become less severe for a time without absolutely ceasing. No existing treatment for psoriasis is both rapidly acting and causes the disease to become less severe for a time without absolutely ceasing. Existing treatments for other inflammatory skin conditions suffer from similar shortcomings.
5-fluorouracil
5-fluorouracil (5-FU) is a cytotoxic antimetabolite that is widely used against solid tumors including gastrointestinal, breast, and head and neck cancers. The efficacy of 5-FU in treating solid tumors is enhanced when 5-FU is used in combination with leucovorin, the calcium salt of folinic acid. (Malet-Martino M et al. Clinical Studies of Three Oral Prodrugs of 5-Fluorouracil (Capecitabine, UFT, S-1): A Review. Oncologist 2002;7(4)288–323).
5-FU is a known treatment for psoriasis. Administration is generally by intravenous catheter. The use of 5-FU is limited by its toxicity and its unpredictable bioavailability. The enzyme dihydropyrimidine dehydrogenase (DPD) deactivates more than 85% of the injected dose of 5-FU. The bioavailability of 5-FU is unpredictable, especially after oral administration. In some patients, where DPD has strong activity, little 5-FU is available. If DPD has weak activity then 5-FU levels are elevated, which may lead to toxicity from overdose. (Malet-Martino et al., supra).
Toxicities of 5-FU include myelosuppression, oral mucositis, diarrhea, nausea, vomiting, cardiotoxicity, and neurotoxicity. Continuous intravenous (IV) infusion of 5-FU may result in the hand-foot syndrome. (Malet-Martino et al., supra) Because of the possibility of severe toxic reactions, it is recommended that patients be hospitalized for, at least, their initial course of therapy with IV 5-FU. (Physician's Desk Reference, 56 edition 2002) The administration of 5-FU by protracted IV infusion is costly and is often associated with infectious and thrombotic complications related to the intravenous catheter. (de Bono J S, Twelves C J. The oral fluorinated pyrimidines. Invest New Drugs 2001; 19(1):41–59).
Because of the low effectiveness, side effects and toxicity of the existing treatments for inflammatory skin conditions, particularly psoriasis, there is a need in the art for an easily administered, efficacious and safe treatment for the disease.
Prodrugs
A prodrug is a pharmacologically inactive compound that is converted into a pharmacologically active agent by a metabolic transformation. In vivo, a prodrug is acted on by naturally occurring enzyme(s) resulting in liberation of the pharmacologically active agent. Prodrugs of 5-FU include capecitabine (N4-pentyloxycarbonyl-5′-deoxy-5-fuorocytidine), 5-fluoro-pyrimidinone (5FP), TS-1 (S-1, ftorafur), FdUMP, 1-(2′-oxopropyl)-5FU, and alkyl-carbonyl-5-FU. Each 5-FU prodrug is enzymatically converted to 5-FU in the body.
Capecitabine
Capecitabine is a preferred 5-FU prodrug of the present invention. Capecitabine is known for use in the treatment of breast and colorectal cancer. Capecitabine has been studied for use in the treatment of advanced gastric cancer, non-small cell lung cancer and pancreatic cancer.
Capecitabine is customarily administered via the oral route, crosses the gastrointestinal barrier intact, and is rapidly and almost completely absorbed by humans. (Malet-Martino et al., supra) Capecitabine is converted into 5-FU in a three-stage process involving several enzymes. In the first step, capecitabine is metabolized to 5′-deoxy-5-fluorocytidine (5′-dFCR) by hepatic carboxylesterase. 5′-dFCR is deaminated to 5′d5-FUrd by cytidine deaminase. 5′d5-FUrd is transformed into 5-FU by thymidine phosphorylase (TP). TP has higher activity in tumor than in normal tissues. (Malet-Martino et al., supra) Capecitabine is preferentially converted to 5-FU at highly angiogenic sites in the body including psoriatic plaques. (Creamer D et al., Overexpression of the angiogenic factor platelet-derived endothelial growth factor/thymidine phosphorylase in psoriatic epidermis. Br J Dermatol December 1997) Capecitabine has an improved therapeutic index over 5-FU because capecitabine increases the concentration of the active principle at the tumor site with a resulting greater activity and decreases the concentration of drug in healthy tissues with a consequent reduction in systemic toxicity.
The most common toxicities of capecitabine are hand-foot syndrome and diarrhea. Other reported toxicities include mucositis, nausea, stomatitis, vomiting, alopecia, fatigue, leopard-like vitiligo, onychomadesis, and onycholysis.
Hand-foot syndrome is an adverse event that occurs more frequently with capecitabine than with 5-FU/leucovorin. Hand-foot syndrome occurred in 53% of patients treated with capecitabine versus 6% of patients treated with 5-FU/leucovorin. In the capecitabine group 17% of patients had the most severe form (grade 3) of hand-foot syndrome versus 1% of patients in the 5-FU/leucovorin group. (Malet-Martino et al., supra) TS-1 also induces hand-foot syndrome. (Elasmar SA et al. Case report: hand-foot syndrome induced by the oral fluorpyrimidine S-1. Jpn J Clin Oncol 2001 April; 31(4):172–4.).
Also known as palmar-plantar erythrodyesthesia, hand-foot syndrome results in painful reddening of the skin of the hands and feet in its mildest form, and in severe pain and loss of skin in its most severe form. The syndrome is graded on a scale between 1 and 3. Patients with Grade 1 disease experience numbness, dysesthesia, tingling, swelling, and erythema. Patients with Grade 2 disease experience painful erythema and swelling that affects activities of daily living. In Grade 3 disease, patients experience moist desquamation, ulceration, blistering, and severe pain that may result in inability to work or perform activities of daily living. (Blum J L et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17:485–493) Hand-foot syndrome initially starts with dysesthesia (an abnormal feeling of discomfort with weight bearing or touch) in the hands and feet, followed by edema and erythema, and ultimately, fissuring and ulceration involving the fingers, toes, palms and plantar aspects of the feet. As the syndrome progresses, the patient may experience extreme pain when grasping objects or walking. Hand-foot syndrome may also affect areas of the body other than the hands and feet, for example areas of the skin to which pressure is applied, such as at the belt or bra line. (Dorr et al. U.S. Pat. No. 6,060,083).
All references cited and discussed in this specification are incorporated herein by reference in their entirety.